Cystic fibrosis (CF) is a disease that arises due to mutations in the gene that codes for cystic fibrosis transmembrane conductance regulator (CFTR), which is a membrane protein involved in chloride ion secretion [1]. Although most cystic fibrosis patients develop chronic progressive disease of the respiratory system, the disease can cause damage to many other organs and tissues. For instance, pancreatic dysfunction , hepatobiliary and genitourinary diseases are all common manifestations of the cystic fibrosis disorder. The diverse array of symptoms and disorders caused by cystic fibrosis have made treatment of the disorder a difficult task. Many treatment modes have focused on improving the clinical symptoms of the particular organ affected in the patient, such as antibiotic treatments, improved nutritional care, and physiotherapy. Additionally, therapies have been developed which attempt to counteract the biochemical basis of the genetic disease, such as gene therapy with CFTR genes. None of these treatment methods, however, has been entirely successful in the treatment of cystic fibrosis.
The most serious consequence of cystic fibrosis (CF) is Pseudomonas aeruginosa lung infection, which by itself accounts for almost 90% of the morbidity and mortality in CF [3]. By age 12, 60-90% of CF patients are infected with P. aeruginosa, and most die before age 30 [3]. Pathogens such as S. aureus and nontypable H. influenzae are also commonly isolated from the respiratory tract of CF patients, but only P. aeruginosa infection has been associated with the progressive decline in pulmonary function in these patients [4-6].
Progressive loss of pulmonary function over many years due to chronic infection with mucoid P. aeruginosa is the hallmark of CF, and yet the connection between lung infection and defects in chloride ion conductance have remained elusive. Smith et al. [2] recently reported defective bacterial killing by fluid obtained from airway epithelial cell cultures of CF patients. Smith et al. reported that this phenomenon was due to the inhibition of an unidentified antimicrobial factor resulting from increased levels of sodium chloride in the airway epithelial fluid.
Many of the severe cases of CF are associated with CFTR mutations leading to greatly reduced to no cell-surface expression of CFTR. The most prevalent of the CFTR mutations is the deletion of phenylalanine 508. Mutant CFTR genes having a deleted phenylalanine 508 are referred to as .DELTA.F508. .DELTA.F508 accounts for approximately 70% of the cystic fibrosis alleles. The .DELTA.F508 mutation has been associated with elevated sweat chloride levels and severe physiological effects such as chronic pulmonary disease in many patients.
Pier et al. has proposed that ingestion and clearance of P. aeruginosa by epithelial cells could be one mechanism by which the epithelial cells protect the lungs against infection [7]. The study reported that ingestion and clearance of P. aeruginosa was compromised in a cell line derived from a patient with the .DELTA.F508 CFTR mutation and was specific for P. aeruginosa among the respiratory pathogens evaluated [7]. Expression of wild-type CFTR by transection, or induction of membrane expression of mutant .DELTA.F508 CFTR by growth of cells at 26.degree. C., increased P. aeruginosa ingestion. Inhibition of ingestion of P. aeruginosa by cells in neonatal mouse lungs increased the total bacterial load in the lungs [7]. These studies showed that CFTR modulated this epithelial cell process but did not specifically indicate how CFTR was involved in the process.